Timing of maternal immune activation and sex influence schizophrenia-relevant cognitive constructs and neuregulin and GABAergic pathways.

Maternal immune activation (MIA) during pregnancy is an established environmental risk factor for schizophrenia. Timing of immune activation exposure as well as sex of the exposed offspring are critical factors in defining the effects of MIA. However, the specificity of MIA on the component structure of schizophrenia, especially cognition, has been difficult to assess due to a lack of translational validity of maze-like testing paradigms. We aimed to assess cognitive domains relevant to schizophrenia using highly translational touchscreen-based tasks in male and female mice exposed to the viral mimetic, poly(I:C) (5 mg/k, i.p.), during early (gestational day (GD) 9-11) and late (GD13-15) gestational time points. Gene expression of schizophrenia candidate pathways were assessed in fetal brain immediately following poly(I:C) exposure and in adulthood to identify its influence on neurodevelopmental processes. Sex and window specific alterations in cognitive performance were found with the early window of MIA exposure causing female-specific disruptions to working memory and reduced perseverative behaviour, while late MIA exposure caused male-specific changes to working memory and deficits in reversal learning. GABAergic specification marker, Nkx2.1 gene expression was reduced in fetal brains and reelin expression was reduced in adult hippocampus of both early and late poly(I:C) exposed mice. Neuregulin and EGF signalling were initially upregulated in the fetal brain, but were reduced in the adult hippocampus, with male mice exposed in the late window showing reduced Nrg3 expression. Serine racemase was reduced in both fetal and adult brain, but again, adult reductions were specific to male mice exposed at the late time point. Overall, we show that cognitive constructs relevant to schizophrenia are altered by in utero exposure to maternal immune activation, but are highly dependent on the timing of infection and the sex of the offspring. Glutamatergic and epidermal growth factor pathways were similarly altered by MIA in a timing and sex dependent manner, while MIA-induced GABAergic deficits were independent of timing or sex.

Addition of eCG to a 14 d prostaglandin treatment regimen in sheep FTAI programs.

In the present study, there was evaluation of the alternative of adding eCG as part of a long-interval prostaglandin-F2α (PG) treatment on the reproductive efficiency of Merino sheep during the breeding season. A total of 210 ewes and 182 ewe lambs were randomly assigned to three experimental groups to induce the timing of estrus among ewes in a: Long-interval PG, group being synchronized using two doses of PG 14 days apart; Long-interval PG + eCG group being synchronized using the same treatment regimen as Group PG with the addition of 200 IU eCG to the regimen, administered concomitantly with the second PG administration; and MAP + eCG group being synchronized with intravaginal progestin sponges for 14 days plus 200 IU eCG, administered at the time of sponge removal. The percentage pregnancy rate in ewes of the MAP + eCG group was greater than the ewes of the Long-interval PG and Long-interval PG + eCG groups (76.4 % compared with 52.0 % and 62.5 %, respectively; P < 0.05). The prolificacy rate was greater in the ewes of the Long-interval PG+eCG group compared with the other groups (114 % compared with 100 % and 103 %, respectively; P < 0.05). When considering the fecundity rate, ewes of the Long-interval PG+eCG and MAP+eCG groups had greater values than ewes of the Long-interval PG group (71.2 % and 78.8 % compared with 52.0 %, respectively; P < 0.05). The Long-interval PG+eCG is an alternative to the conventional progestin sponge plus eCG treatment regimen with there being a greater fecundity rate when this regimen is used compared with the Long-term PG and similar to MAP-eCG treatment regimens.

Bazedoxifene - a promising brain active SERM that crosses the blood brain barrier and enhances spatial memory.

Over 20 years of accumulated evidence has shown that the major female sex hormone 17ß-estradiol can enhance cognitive functioning. However, the utility of estradiol as a therapeutic cognitive enhancer is hindered by its unwanted peripheral effects (carcinogenic). Selective estrogen receptor modulators (SERMs) avoid the unwanted effects of estradiol by acting as estrogen receptor antagonists in some tissues such as breast and uterus, but as agonists in others such as bone, and are currently used for the treatment of osteoporosis. However, understanding of their actions in the brain are limited. The third generation SERM bazedoxifene has recently been FDA approved for clinical use with an improved biosafety profile. However, whether bazedoxifene can enter the brain and enhance cognition is unknown. Using mice, the current study aimed to explore if bazedoxifene can 1) cross the blood-brain barrier, 2) rescue ovariectomy-induced hippocampal-dependent spatial memory deficit, and 3) activate neural estrogen response element (ERE)-dependent gene transcription. Using liquid chromatography-mass spectrometry (LC-MS), we firstly demonstrate that a peripheral injection of bazedoxifene can enter the brain. Secondly, we show that an acute intraperitoneal injection of bazedoxifene can rescue ovariectomy-induced spatial memory deficits. And finally, using the ERE-luciferase reporter mouse, we show in vivo that bazedoxifene can activate the ERE in the brain. The evidence shown here suggest bazedoxifene could be a viable cognitive enhancer with promising clinical applicability.

Barriers to the implementation of new guidelines among pediatric surgeons: online survey.

PURPOSE: To identify barriers that prevent pediatric surgeons from implementing updated practice guidelines. METHODS: An online survey targeting pediatric surgeons was conducted on the StayCurrent MD Application (SCMA) and Pediatric Surgery Education Facebook page (PSE FBP). The survey results for pediatric surgeons of underdeveloped countries (PSUC) and pediatric surgeons of developed countries (PSDC) was compared and analyzed. RESULTS: Based on the number of active members on PSE FBP and SCA, the response rate was 32.3% (174/539), 66.3% of responses were from PSUC. The majority of PSUC (73%) wanted to have convincing guidelines and the plurality of PSDC (46%) wanted to see approval by the American Pediatric Surgical Association (APSA) for implementation of new guidelines. Lack of resources was the number one response (78%) for PSUC not implementing the most up to date guidelines and about 40% of the PSDC responded "concerned about malpractice liability." CONCLUSIONS: PSUC and PSDC identified very different barriers to implementation of new guidelines. It is reassuring that accessibility to treatment is not the primary issue, though resistance to implementation is a resounding concern. Identifying the barriers will highlight areas that need to be addressed, and awareness may help resolve some of the barriers.

Developing a craniomaxillofacial and cervical equipment module for surgeons in the austere environment: a systematic review.

The treatment of craniomaxillofacial and cervical wounds in a disaster relief setting is done by clinicians from local medical treatment facilities, non-governmental organisations (NGO), or the military. Although each group and individual surgeon will need specific equipment, this will be restricted by weight, portability and interoperability. We systematically reviewed scientific and commercial publications according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The papers we identified described the portable equipment that is required to treat patients who need damage-control surgery (decompressive craniectomy, temporary stabilisation, and internal and external fixation of the facial bones) for craniomaxillofacial and cervical injuries in austere or military settings. Austere settings are those in which there is an inherent lack of infrastructure, such as facilities, roads, and power. A total of 35 papers or scientific articles recommended the equipment that is needed to manage these injuries, but we could find no module that was specifically designed for use in these environments. Multiple modules are currently required to provide comprehensive surgical care and many of the items in the existing maxillofacial and neurosurgical kits are rarely used, which increases the cost of initial procurement and resupply. Duplications in equipment between modules also increase the size, weight, and financial cost. We suggest the equipment that is required to make up a rationalised, lightweight, and compact module that can be used for all craniomaxillofacial and cervical operations in austere settings.

Effect of GnRH or hCG administration on Day 4 post insemination on reproductive performance in Merino sheep of North Patagonia.

Different therapeutic strategies have been used with the objective of improve luteal function to reduce embryonic losses. The objective of this work was to study the effect of the administration of GnRH or hCG at Day 4 post fixed time artificial insemination (FTAI) on reproductive efficiency in Merino sheep during the breeding season in North Patagonia. Estrus of multiparous Merino ewes (n = 288) was synchronized by two injections of prostaglandins (PG; 125 µg, Cloprostenol), 14 days apart. Cervical FTAI was performed 53-56 h after the second PG with a dose of fresh semen (100 × 106 spermatozoa) from five Merino rams. In all ewes body condition score (BCS) was determined at FTAI. At 4 days post FTAI ewes were randomly assigned into three experimental groups: GnRH group (4 µg, Buserelin; n = 99), hCG group (300 IU, hCG; n = 92) and Control group (1 ml, saline solution; n = 97). Pregnancy and pregnancy losses were evaluated by ultrasonography on Days 33 and 90 post FTAI. Additionally, embryo crown-rump length (CRL) was measured by ultrasonography (n = 12 single-pregnant ewes by experimental group) at the first ultrasound. Date of birth, litter size and lamb weight were recorded (n = 111 pregnant ewes). Pregnancy rate on Days 33 and 90 post FTAI did not differ among treatment groups (P > 0.05). Pregnancy losses at Day 33 post FTAI were lower in the hCG group compared to the GnRH and Control groups (0, 3, 7.2%, respectively; P < 0.05). Pregnancy losses between Days 33 and 90 after FTAI were negligible (P > 0.05). The embryo CRL at Day 33 post FTAI was not increased by the hormonal treatments (P > 0.05). Moreover, it was lower in GnRH group compared to Control group (P < 0.05). Litter size tended to be greater in the GnRH group compared to the hCG and Control groups (P < 0.1). The birth weight of twin lambs tended to be higher in the GnRH group compared to the Control group (P < 0.1). The birth weight of single lambs was not affected by treatments (P > 0.05). Ram fertility and BCS of ewes at FTAI influenced the effect of hormonal treatments on reproductive parameters. In conclusion, administration of hCG or GnRH at Day 4 post FTAI does not improve pregnancy rate but treatment with hCG reduces pregnancy loss on Day 33 post FTAI. GnRH treatment improves litter size and twin lambs birth weight.

Skill sets required for the management of military head, face and neck trauma: a multidisciplinary consensus statement.

INTRODUCTION: The evolution of medical practice is resulting in increasing subspecialisation, with head, face and neck (HFN) trauma in a civilian environment usually managed by a combination of surgical specialties working as a team. However, the full combination of HFN specialties commonly available in the NHS may not be available in future UK military-led operations, necessitating the identification of a group of skill sets that could be delivered by one or more deployed surgeons. METHOD: A systematic review was undertaken to identify those surgical procedures performed to treat acute military head, face, neck and eye trauma. A multidisciplinary consensus group was convened following this with military HFN trauma expertise to define those procedures commonly required to conduct deployed, in-theatre HFN surgical combat trauma management. RESULTS: Head, face, neck and eye damage control surgical procedures were identified as comprising surgical cricothyroidotomy, cervico-facial haemorrhage control and decompression of orbital haemorrhage through lateral canthotomy. Acute in-theatre surgical skills required within 24 hours consist of wound debridement, surgical tracheostomy, decompressive craniectomy, intracranial pressure monitor placement, temporary facial fracture stabilisation for airway management or haemorrhage control and primary globe repair. Delayed in-theatre procedures required within 5 days prior to predicted evacuation encompass facial fracture fixation, delayed lateral canthotomy, evisceration, enucleation and eyelid repair. CONCLUSIONS: The identification of those skill sets required for deployment is in keeping with the General Medical Council's current drive towards credentialing consultants, by which a consultant surgeon's capabilities in particular practice areas would be defined. Limited opportunities currently exist for trainees and consultants to gain experience in the management of traumatic head, face, neck and eye injuries seen in a kinetic combat environment. Predeployment training requires that the surgical techniques described in this paper are covered and should form the curriculum of future military-specific surgical fellowships. Relevant continued professional development will be necessary to maintain required clinical competency.

Towards global consensus on core outcomes for hidradenitis suppurativa research: an update from the HISTORIC consensus meetings I and II.

BACKGROUND: A core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed-upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e-Delphi surveys. In this manuscript, we describe two in-person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items. OBJECTIVES: To consider which items from a long list of candidate items to exclude and which to cluster into outcome domains. METHODS: The study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey. RESULTS: Forty-one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS-specific quality of life, satisfaction, symptoms, pain and global assessments. CONCLUSIONS: The HISTORIC consensus meetings I and II will be followed by further e-Delphi rounds to finalize the core domain set, building on the work of the in-person consensus meetings.

Hormonal therapeutic strategy on the induction of accessory corpora lutea in relation to follicle size and on the increase of progesterone in sheep.

We determined the effect of GnRH or hCG treatment on day 4 post-time artificial insemination (FTAI) on the formation of accessory corpora lutea (acc-CL) and on the concentration of serum progesterone (P4) in sheep. Multiparous adult Merino ewes (n = 36) were synchronized for estrus using double injection of PGF2α agonist (125 µg Cloprostenol) with an interval of 14 days. At 53-56 h after the second PG application, FTAI was performed. On day 4 post FTAI, ewes were either treated with analogue of GnRH (4 µg buserelin; n = 12) or hCG (300 IU, hCG; n = 12) or saline solution (1 ml; Control; n = 12). Two laparoscopic ovarian examinations were performed on days 4 and 10 post FTAI. In the first observation, we determined the number of post ovulation corpora lutea (po-CL) and the site, number and diameter of follicles present in both ovaries. In the second laparoscopy, we observed the number of po-CL and acc-CL. The sizes of the follicles that generated the acc-CL were determined according to the position of the follicles observed in the first laparoscopy. Serum P4 concentration was determined on days 4, 7, 10, 13, 17 and 21 post FTAI by chemiluminescence. A similar follicular population in size and number was observed in the three experimental groups prior to the beginning of treatments (Follicles 2 mm: 6.4 ± 3.7, 3 mm: 3.0 ± 2.3, 4 mm: 1.1 ± 0.5, 5 mm: 1.4 ± 0.8; P Ëƒ 0.05). The formation of 1.0 ± 0.4 and 1.1 ± 0.3 acc-CL was observed in the GnRH and hCG groups, respectively (P Ëƒ 0.05), but was not observed in the Control group (P < 0.05). Follicle sizes from which acc-CL generated were 3, 4 and 5 mm and did not differ between hormonal treatments (P Ëƒ 0.05). The hCG group had higher mean concentrations of P4 on days 7, 10, 13 and 17 post FTAI compared with the GnRH group and the Control group (P < 0.05), while no differences were observed between these two latter groups (P > 0.05). Mean P4 concentrations in ewes treated with hCG showed no differences according to the size of the follicle from which acc-CL were generated (P Ëƒ 0.05). In conclusion, administration of hCG or GnRH on day 4 post FTAI induced the formation of one acc-CL from follicles of 3, 4 or 5 mm, indistinctly. However, serum P4 concentration increased significantly only in the hCG group. The serum P4 concentrations of acc-CL that originated from different follicle sizes did not differ.

Contemporary management of maxillofacial ballistic trauma.

Ballistic maxillofacial trauma in the UK is fortunately relatively rare, and generally involves low velocity handguns and shotguns. Civilian terrorist events have, however, shown that all maxillofacial surgeons need to understand how to treat injuries from improvised explosive devices. Maxillofacial surgeons in the UK have also been responsible for the management of soldiers evacuated from Iraq and Afghanistan, and in this review we describe the newer types of treatment that have evolved from these conflicts, particularly that of damage-control maxillofacial surgery.

Assessing Tn5 and Sleeping Beauty for transpositional transgenesis by cytoplasmic injection into bovine and ovine zygotes.

Transgenic domestic animals represent an alternative to bioreactors for large-scale production of biopharmaceuticals and could also provide more accurate biomedical models than rodents. However, their generation remains inefficient. Recently, DNA transposons allowed improved transgenesis efficiencies in mice and pigs. In this work, Tn5 and Sleeping Beauty (SB) transposon systems were evaluated for transgenesis by simple cytoplasmic injection in livestock zygotes. In the case of Tn5, the transposome complex of transposon nucleic acid and Tn5 protein was injected. In the case of SB, the supercoiled plasmids encoding a transposon and the SB transposase were co-injected. In vitro produced bovine zygotes were used to establish the cytoplasmic injection conditions. The in vitro cultured blastocysts were evaluated for reporter gene expression and genotyped. Subsequently, both transposon systems were injected in seasonally available ovine zygotes, employing transposons carrying the recombinant human factor IX driven by the beta-lactoglobulin promoter. The Tn5 approach did not result in transgenic lambs. In contrast, the Sleeping Beauty injection resulted in 2 lambs (29%) carrying the transgene. Both animals exhibited cellular mosaicism of the transgene. The extraembryonic tissues (placenta or umbilical cord) of three additional animals were also transgenic. These results show that transpositional transgenesis by cytoplasmic injection of SB transposon components can be applied for the production of transgenic lambs of pharmaceutical interest.

Optimising ballistic facial coverage from military fragmenting munitions: a consensus statement.

VIRTUS is the first United Kingdom (UK) military personal armour system to provide components that are capable of protecting the whole face from low velocity ballistic projectiles. Protection is modular, using a helmet worn with ballistic eyewear, a visor, and a mandibular guard. When all four components are worn together the face is completely covered, but the heat, discomfort, and weight may not be optimal in all types of combat. We organized a Delphi consensus group analysis with 29 military consultant surgeons from the UK, United States, Canada, Australia, and New Zealand to identify a potential hierarchy of functional facial units in order of importance that require protection. We identified the causes of those facial injuries that are hardest to reconstruct, and the most effective combinations of facial protection. Protection is required from both penetrating projectiles and burns. There was strong consensus that blunt injury to the facial skeleton was currently not a military priority. Functional units that should be prioritised are eyes and eyelids, followed consecutively by the nose, lips, and ears. Twenty-nine respondents felt that the visor was more important than the mandibular guard if only one piece was to be worn. Essential cover of the brain and eyes is achieved from all directions using a combination of helmet and visor. Nasal cover currently requires the mandibular guard unless the visor can be modified to cover it as well. Any such prototype would need extensive ergonomics and assessment of integration, as any changes would have to be acceptable to the people who wear them in the long term.

Cerebroplacental ratio in pregnancies complicated by gestational diabetes mellitus.

OBJECTIVE: To assess the relationship between the cerebroplacental ratio (CPR) and intrapartum and perinatal outcomes in pregnancies complicated by gestational diabetes mellitus (GDM). METHODS: This was a retrospective cohort study of women with a non-anomalous singleton pregnancy diagnosed with GDM who delivered at Mater Mothers' Hospital between 2007 and 2015. CPR was measured in 1089 cases between 34 + 0 and 36 + 6 weeks' gestation. CPR values were compared between groups categorized according to GDM treatment (by diet, oral hypoglycemic agent (OHA) or insulin). The association between CPR and intrapartum and perinatal outcomes was evaluated. RESULTS: No difference in CPR was observed between treatment groups. Fetuses with CPR < 10th centile were significantly more likely to have adverse composite perinatal outcome (odds ratio (OR) = 2.93 (95% CI, 1.95-4.40)), preterm delivery and low birth weight than fetuses with CPR ≥ 10th centile (all P < 0.001). These associations were present regardless of the type of GDM treatment. Fetuses of women with insulin-controlled GDM had poorer neonatal outcomes than did fetuses of women treated with OHA or dietary control alone. The risk of adverse outcome was significantly increased in the insulin-treated group (OR = 1.75 (95% CI, 1.34-2.28); P < 0.001), which also had higher rates of preterm delivery and higher birth weight. CONCLUSION: Regardless of the type of treatment, a low CPR is associated with poorer neonatal outcome in women with GDM. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prevalence of cervical cancer and associated mortality in Grenada, 2000-2010.

Objective To assess cervical cancer prevalence and associated mortality in Grenada, West Indies during 2000-2010. Methods Records of visits to hospital and clinical facilities were obtained from the histopathology laboratory of the Grenada General Hospital. Records were de-identified and electronically compiled. Cervical cancer prevalence was assessed via cross-sectional analysis of this secondary data. Of a total 12 012 records, 2 527 were selected for analysis using sampling without replacement. Cases were matched to corresponding patient data from death registries, where possible, and used to calculate associated mortality rates. Results The observed prevalence of cervical cancer was 52.4 per 100 000 women (ages 15 and above). The highest rates of cervical cancer occurred in the 35-44 age group, with the second highest among 45-64-year-olds. A total of 65 deaths were attributable to cervical cancer during 2000-2010, more than 50% of which were among women > 65 years old. The observed mortality rate was 16.7 per 100 000, almost twice the rate estimated by WHO for the region. Conclusions This study demonstrates the need for a comprehensive cervical cancer-screening program in Grenada. Results should contribute to informing future studies on how to appropriately generate and execute public health policy for education, screening, prevention, and control of cervical cancer in Grenada.

Photochemistry of forbidden oxygen lines in the inner coma of 67P/Churyumov-Gerasimenko.

Observations of the green and red-doublet emission lines have previously been realized for several comets. We present here a chemistry-emission coupled model to study the production and loss mechanisms of the O(1S) and O(1D) states, which are responsible for the emission lines of interest for comet 67P/Churyumov-Gerasimenko. The recent discovery of O2 in significant abundance relative to water 3.80 ± 0.85% within the coma of 67P has been taken into consideration for the first time in such models. We evaluate the effect of the presence of O2 on the green to red-doublet emission intensity ratio, which is traditionally used to assess the CO2 abundance within cometary atmospheres. Model simulations, solving the continuity equation with transport, show that not taking O2 into account leads to an underestimation of the CO2 abundance within 67P, with a relative error of about 25%. This strongly suggests that the green to red-doublet emission intensity ratio alone is not a proper tool for determining the CO2 abundance, as previously suggested. Indeed, there is no compelling reason why O2 would not be a common cometary volatile, making revision of earlier assessments regarding the CO2 abundance in cometary atmospheres necessary. The large uncertainties of the CO2 photodissociation cross section imply that more studies are required in order to better constrain the O(1S) and O(1D) production through this mechanism. Space weather phenomena, such as powerful solar flares, could be used as tools for doing so, providing additional information on a good estimation of the O2 abundance within cometary atmospheres.

Pre-Selection Test to Identify High Responder Donor Goats.

The aim of the study was to evaluate the feasibility of pre-selection of high or low responder does prior to the superovulatory protocols. Twenty Saanen does received 800 IU of equine chorionic gonadotropin (eCG) at the end of long-term progestogen treatment. Fourteen days later, a second progestogen protocol associated with a multiple-dose follicle stimulation hormone (FSH) treatment (5 IU/kg of FSH, in six decreasing doses between days 4 to 6 of the protocol) was administered. Transrectal ultrasound was used to assess the follicular status at the beginning of superovulatory treatments, at the oestrous onset and on the seventh day of the oestrous cycle for counting corpora lutea (CL). A significant lower number of CL was obtained in eCG-treated in comparision with FSH-treated does (p < 0.05). A quartic regression was able to explain the relationship between the number of CL in response to both treatments (r(2) =0.50; p < 0.05). Seventy per cent (14 of 20) of does maintained the same ovulatory response (high or low) after treatments. The Kappa (κ = 0.40; p < 0.05) and Spearman (rs = 0.39; p = 0.08) coefficients were able to show a relationship between treatments. Regarding the follicular status, there is a significant relationship between the number of small follicles (r = 0.71; r(2) =0.47; p < 0.01) and total follicles (r = 0.60; p < 0.01) at eCG and first FSH dose with the number of CL. Moreover, it was found a negative relationship between the presence of large follicles and the number of CL in response to eCG treatment (r = -0.44; p < 0.05), but not from FSH (p > 0.05). In conclusion, the screening test with eCG has the potential to identify Saanen does that will better respond to the superovulatory protocol with FSH. In addition, it highlighted the importance of an ultrasound evaluation prior to the beginning of superovulatory treatments with FSH to characterize the follicular status and identify the potential donors of high ovulatory response in MOET programmes in goats.